DOI: 10.1002/chem.201406044

Communication

& Asymmetric Catalysis

Brønsted Acid-Catalyzed, Highly Enantioselective Addition of Enamides to In Situ-Generated ortho-Quinone Methides: A Domino Approach to Complex Acetamidotetrahydroxanthenes Satyajit Saha and Christoph Schneider*[a] that have attracted considerable attention over the years as a result of their wide range of biological properties, such as analgesic, antiviral, anti-inflammatory and antibacterial activities.[11] We recently reported the phosphoric acid-catalyzed, highly enantioselective conjugate addition of 1,3-dicarbonyl compounds to in situ generated o-QMs and their application to the high-yielding one-pot synthesis of 4-aryl-4H-chromenes and related heterocycles through a subsequent cyclodehydration reaction (Scheme 1, pathway a).[12] As substrates for the in situ

Abstract: The highly enantioselective conjugate addition of enamides and enecarbamates to in situ-generated ortho-quinone methides, upon subsequent N,O-acetalization, gives rise to acetamido-substituted tetrahydroxanthenes with generally excellent enantio- and diastereoselectivities. A chiral BINOL-based phosphoric acid catalyst controls the enantioselectivity of the carbon–carbon bond-forming event. The products are readily converted into other xanthene-based heterocycles.

Ortho-Quinone methides (o-QMs), featuring a unique assembly of carbonyl and olefinic moieties in close proximity, have been known for more than one century in organic chemistry and exist in nature in a variety of medicinally important natural products.[1] Because of their inherent highly electrophilic character as highly polarized 1-oxabutadienes, they react readily with a broad range of nucleophiles and the thrust for aromatization adds to the driving force for such conjugate additions. Accordingly, they participate in many chemical, medicinal, and biological processes, such as lignin biosynthesis, enzyme inhibition, and DNA alkylation and cross-linking.[2] Although the chemistry of o-QMs has been studied quite extensively, mainly in conjugate additions, [4+2]-cycloadditions, and 6p-electrocyclization reactions,[3] reports on catalyst-controlled, enantioselective reactions with o-QMs as substrates are limited. Seminal contributions to this field have been disclosed by the groups of Sigman,[4] Lectka,[5] Schaus,[6] Ye,[7] and Scheidt,[8] who studied enantioselective palladium-, cinchona alkaloid-, BINOL-, and NHC-catalyzed reactions of o-QMs, respectively, with great success. Of particular relevance to the present study were findings by the groups of Rueping[9] and Bach,[10] which revealed the capacity of chiral phosphoric acids to activate ortho-hydroxy benzyl alcohols for ensuing intramolecular allylic alkylation reactions and indole alkylation reactions, respectively. Xanthenes and in particular benzo-fused xanthenes constitute an important class of compounds in organic chemistry [a] Dr. S. Saha, Prof. Dr. C. Schneider Institut fr Organische Chemie, Universitt Leipzig Johannisallee 29, 04103 Leipzig (Germany) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201406044. Chem. Eur. J. 2015, 21, 2348 – 2352

Scheme 1. Brønsted acid-catalyzed reaction of o-QM with 1,3-diketones (pathway a) and with enamides (pathway b).

preparation of o-QMs, we employed ortho-hydroxybenzhydryl alcohols 1, which were converted into the reactive o-QMs through acid-catalyzed dehydration. This methodology was, however, restricted to reactive nucleophiles with sufficiently high enol content and could not be extended to simple ketones. Alternatively, enamides carrying an electron-withdrawing group on the nitrogen atom constitute stable ketone enol surrogates and have been employed as highly reactive nucleophiles in various carbon–carbon bond-forming reactions under Lewis acid and Brønsted acid catalysis.[13] As an additional design element, which was expected to support a highly ordered transition state in the present reaction, they carry an acidic proton on the nitrogen atom, which offers the possibility of forming an additional hydrogen bond between the chiral catalyst and the nucleophile. We report herein the first catalytic and highly enantioselective conjugate addition of enamides and enecarbamates towards in situ-generated o-QMs under chiral Brønsted acid catalysis (Scheme 1, pathway b). In a novel domino conjugate addition–N,O-acetalization process, a broadly applicable and high-yielding synthesis of highly functionalized acetamido-substituted tetrahydroxanthenes has been developed, which rou-

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Communication tinely affords the products with excellent diastereo- and enantioselectivities. We started our studies by examining the reaction of orthohydroxybenzhydryl alcohol 1 a (1 equiv) with N-(3,4-dihydronaphthalen-1-yl)acetamide 2 a (1.2 equiv) in CH2Cl2 in the presence of various chiral phosphoric acids 3 (5 mol %; Table 1). Although simple 3,3’-phenyl-substituted BINOL-phosphoric acid 3 a gave rise to only poor enantioselectivity in this reaction (Table 1, entry 1), the use of sterically more demanding 3,3’-aryl substituents in the BINOL-backbone of the phosphoric acids led to a significant increase in enantioselectivity. When for example phosphoric acid 3 b, with mesityl groups as 3,3’-substituents, was employed as Brønsted acid catalyst, the addition product 4 a was isolated in 77 % yield as a single diastereomer and with 97:3 e.r. after stirring for 12 h in CH2Cl2 at room temperature (Table 1, entry 2). Phosphoric acid 3 d, with a larger para-substituent on the 3,3’-aryl groups, further increased the e.r. to 98:2 (Table 1, entry 4), whereas catalyst 3 e, with pentamethylated 3,3’phenyl groups, was found to be the optimal catalyst for this reaction, giving the highest enantiomeric ratio of 99:1 in combination with a complete diastereoselectivity (Table 1, entry 5). Surprisingly, structurally similar catalysts 3 c, 3 g, and 3 h were found to be largely unreactive in this reaction, suggesting that too much steric congestion in the catalyst backbone had shut

Table 2. Brønsted acid-catalyzed addition of enamides 2 a and 2 b to ortho-hydroxy benzhydrols 1.[a–d]

Table 1. Optimization studies.[a]

Entry

Cat.

Solvent

t [h]

Yield [%][b]

1 2 3 4 5 6 7 8 9 10[e]

3a 3b 3c 3d 3e 3f 3g 3h 3e 3e

CHCl3 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CHCl3 CH2Cl2

48 12 12 10 12 12 12 14 12 12

62 77 —[f] 78 76 79 —[f] —[f] 77 83

d.r.[c] > 98:2 > 98:2 —[g] > 98:2 > 98:2 > 98:2 —[g] —[g] > 98:2 > 98:2

e.r.[d] 57:43 97:3 —[g] 98:2 99:1 97:3 —[g] —[g] 99:1 99:1

[a] Reaction conditions: 1 a–m (0.42 mmol, 1 equiv), cyclic enamide 2 a/ 2 b (0.50 mmol, 1.2 equiv), 4  MS (catalytic amount), catalyst 3 e (13 mg, 5 mol %), CH2Cl2 (4 mL), RT, 12–84 h; [b] yield of the isolated major diastereomer; [c] determined from 1H NMR spectrum of the crude product; [d] e.r. determined through chiral HPLC analysis (see the Supporting Information).

[a] Reaction conditions: 1 a (0.23 mmol, 1 equiv), 2 a (0.27 mmol, 1.2 equiv), catalyst 3 (5 mol %) CH2Cl2 (2 mL), RT; [b] yield of the isolated major diastereomer; [c] determined from 1H NMR spectrum of the crude product; [d] e.r. determined through chiral HPL analysis (see the Supporting Information); [e] small amount of 4  MS (5 mg per 0.23 mmol of 1 a) was used; [f] slow reaction; [g] not determined.

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Communication down the reactivity in these cases (Table 1, entries 3, Table 3. Brønsted acid-catalyzed addition of enamides 2 c-g to ortho-hydroxy benzhy7, and 8). A brief solvent screening revealed that didrols 1.[a–d] chloromethane was superior to the other solvents that were investigated (see the Supporting Information, Table S1). Gratifyingly, we found that the addition of activated powdered molecular sieves (4 ) further improved the chemical yield of the reaction without compromising the enantioselectivity (Table 1, entry 10). We assume that the molecular sieves trap the equimolar amount of water that is generated in the reaction, preventing the undesired decomposition of the nucleophile. To evaluate the scope of this process, various ortho-hydroxybenzhydrols 1 a–m were subsequently subjected to the above-optimized reaction conditions in the presence of enamides 2 a and 2 b (Table 2). In all cases studied, the reaction proceeded smoothly, typically within 1–2 days, and furnished pure or almost pure diastereomers in typically good yields with excellent enantioselectivity. A range of functional groups were readily tolerated at various positions both within the quinone methide fragment and within the b-aryl substituent, delivering the products with excellent results. A crystal structure of xanthene 4 l, obtained from MeOH, revealed both the relative and absolute configuration of the products, which was assigned to all other products as well (Figure 1).[14] To further broaden the scope of this reaction with respect to the enamide component, we employed some more carbocyclic and heterocyclic enamides in this process, all of which produced the desired products with excellent selectivity (Table 3). Thus, using the chromene- and thiochromenebased enamides 2 c and 2 d as nucleophiles, the corresponding acetamido-substituted chromeno[4,3b]chromenes 6 a and 6 b and thiochromeno[4,3[a] All reactions were carried out on 0.2 mmol scale; [b] yield of the isolated major diab]chromenes 7 a and 7 b, respectively, were obtained stereomer; [c] determined from 1H NMR spectrum of the crude product; [d] e.r. deterin good yields and exceptional diastereo- and enanmined through chiral HPLC analysis (see the Supporting Information). tioselectivities under the described conditions (Table 3). In addition, the influence of the N-protecting group in the Interestingly, the regioisomeric enamide 2 e delivered the enamide component was briefly investigated in this study. Eneacetamido-substituted benzo[a]xanthenes 8 a and 8 b in good carbamate 2 h performed extremely well both in terms of yield yields, albeit with decreased selectivity. Enamide 2 f lacking the and enantioselectivity (Scheme 2). Upon subsequent eliminaannelated aromatic ring also conferred the addition products 9 a and 9 b in good yields, excellent diastereoselectivity and e.r. up to 92:8. Ring-enlarged, benzofused cyclohepta[1,2b]chromenes 10 a and 10 b were easily accessed as well starting from the seven-membered ring-based enamide 2 g in good to moderate enantiomeric ratios (Table 3). To further reveal the synthetic potential of this new process, several of the products were subsequently converted into versatile dihydrobenzo[c]xanthenes and related heterocycles 11 a– f through an acid-catalyzed elimination of acetamide (Table 4). The reactions generally occurred with excellent yields (> 90 %) and the products completely retained their optical Scheme 2. Brønsted acid-catalyzed addition of enecarbamate 2 h to orthopurity. hydroxybenzhydrol 1 a. Chem. Eur. J. 2015, 21, 2348 – 2352

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Communication To further expand this protocol, the Brønsted acid-catalyzed addition of 1,3-cyclohexanedione-derived enamide 2 i to the oQM derived from 1 a was carried out, affording the desired product 13 in very good yield and enantiomeric ratio and as a single diastereomer (Scheme 3). These observations substantially enhance the scope and applicability of this methodology and allow for elaboration of these scaffolds in library synthesis.

Scheme 3. Brønsted acid-catalyzed addition of enamide 2 i to ortho-hydroxy benzhydrol 1 a.

On the basis of the crystal structure that we obtained for xanthene 4 l, we propose a transition structure, as shown in Figure 2. We assume that the chiral phosphoric acid works as a bifunctional catalyst that is hydrogen-bonded to the orthoquinone methide and at the same time attached to the enamide N H moiety through an additional hydrogen bridge from

Figure 1. Crystal structure of xanthene 4 l. Thermal ellipsoids are set to 50 % probability.

Table 4. Acid-promoted elimination of acetamide.[a–c]

Figure 2. Proposed transition state assembly.

[a] All reactions were carried out on 0.2 mmol scale; [b] yield of the isolated product; [c] e.r. determined through chiral HPLC analysis (see the Supporting Information).

tion with trifluoroacetic acid (TFA), dihydrobenzo[c]xanthene 11 a was obtained in 72 % overall yield and with 98:2 e.r. Chem. Eur. J. 2015, 21, 2348 – 2352

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the basic phosphoryl oxygen atom. In this highly ordered transition state assembly, the top face of the o-QM is effectively shielded by the neighboring Ar2 group in the catalyst’s backbone and the conjugate addition preferentially occurs from the bottom side. This transition state assembly would also rationalize the observed trans diastereoselectivity of the reaction. In summary, we have developed a highly efficient, Brønsted acid-catalyzed, conjugate addition of enamides to in situ-generated ortho-quinone methides followed by a N,O-acetalization reaction, both of which proceeded with exceptional stereocontrol. A broad range of highly functionalized acetamido-substituted tetrahydroxanthenes and related heterocycles were obtained with typically good to very good yields and excellent enantioselectivities. Several of the products were subsequently converted into dihydroxanthenes through an acid-catalyzed

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Communication elimination reaction with full retention of absolute configuration. This study further extends the concept of phosphoric acid-catalyzed, enantioselective reactions of ortho-quinone methides and suggests that a broad range of additional nucleophiles may be employed accordingly.

[5] [6] [7]

[8]

Acknowledgements We are grateful to Dr. P. Lçnnecke (University of Leipzig) for the crystal structure analysis. We gratefully acknowledge the donation of chemicals from Evonik and BASF.

[10]

Keywords: asymmetric catalysis · Brønsted acids · domino reactions · organocatalysis · xanthenes

[11]

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Received: August 13, 2014 Published online on December 8, 2014

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Brønsted acid-catalyzed, highly enantioselective addition of enamides to in situ-generated ortho-quinone methides: a domino approach to complex acetamidotetrahydroxanthenes.

The highly enantioselective conjugate addition of enamides and enecarbamates to in situ-generated ortho-quinone methides, upon subsequent N,O-acetaliz...
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